The p75 neurotrophin receptor (p75NTR) has been known to play multiple roles in cell survival and apoptosis (Friedman, 2000; Maggirwar et al., 1998; Rabizadeh et al., 1993), axonal growth (Bentley and Lee, 2000), and cell differentiation (Hosomi et al., 2003). This multifunctional receptor is more widely expressed during development than in adults (Friedman, 2000; Yan and Johnson, 1988). However, it is reexpressed in the brain after injury or in disease (Casha et al., 2001; Kokaia et al., 1998; Ramos et al., 2007; Roux et al., 1999; Yaar et al., 1997). Although previous studies demonstrated that p75NTR is induced by seizure in neurons, where it causes apoptosis, (Roux et al., 1999; Volosin et al., 2008), the mechanisms involved in regulating p75NTR expression after brain injury are unknown. The immediate response that occurs in many pathological conditions is the production of proinflammatory cytokines. Thus, I hypothesized that those essential proinflammatory cytokines may be responsible for the reexpression of p75NTR seen following brain injury or in disease. Using both in vitro and in vivo methods, this thesis evaluated the mechanisms that regulate p75NTR after cytokine treatment in distinct cellular contexts and the functional consequences of p75NTR expression on neuronal death. The results demonstrated that IL-1β and TNFα induce p75NTR expression in neurons and astrocytes by distinct signaling mechanisms. Moreover, IL-1β exacerbates proNGF-mediated neuronal death by recruiting sortilin receptor and p75NTR to the cell surface. IL-1β preferentially induces the monomeric forms of p75NTR, which associates with sortilin and is sufficient to activate proNGF mediated apoptotic signaling. IL-1β increases p75NTR expression and increases NGF in vivo without the context of injury, but does not induce cell death. Overall, these results suggest that IL-1β release following injury or in disease may facilitate proNGF-mediated cell death by regulating surface expression of the p75NTR-sortilin complex to exacerbate neuronal death after injury that can be activated by proneurotrophins.
Subject (authority = RUETD)
Topic
Biology
Subject (authority = ETD-LCSH)
Topic
Neurotransmitter receptors
Subject (authority = ETD-LCSH)
Topic
Cytokines
Subject (authority = ETD-LCSH)
Topic
Cytology--Research
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
RelatedItem (type = host)
TitleInfo
Title
Graduate School - Newark Electronic Theses and Dissertations
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